The present invention relates to new salts of S-adenosyl-1-methionine.
This patent relates to new salts of S-adenosyl-1-methionine (known as SAM-e) with polycations, the processes for obtaining them and to therapeutic uses of these new salts. More particularly, the invention relates to salts deriving from the reaction between SAM-e, SAM-e salts and polycations such as chitosan, their production process, and pharmaceutical compositions that contain them as active principles.
SAM-e is a naturally occurring substance that is present in all living organisms and has a number of very important biological functions. SAM-e exists in two enantiomeric forms as (S,S) S-adenosyl-1-methionine and (R,S) S-adenosyl-1-methionine. Among these functions are the following:
methyl group donor in transmethylation reactions (it is the sole methyl group donor in such reactions-including methylation of DNA, proteins, hormones, catechol and indoleamines and phosphatidylethanolamine to phosphatidylcholine); it is a substrate of an enzyme lyase that converts S-adenosyl-1-methionine to the molecule methylthioadenosine and homoserine; it is an aminobutyric chain donor to tRNA; it is an aminoacidic chain donor in the biosynthesis of biotin; SAM, after decarboxylation, is the donor of aminopropyl groups for the biosynthesis of neuroregulatory polyamines spermidine and spermine. (Zappia et al (1979) Biomedical and Pharmacological roles of Adenosylmethionine and the Central Nervous System, page 1, Pergamon Press. NY.)
SAM has been used clinically for more than twenty years in the treatment of liver disease (Friedel H, Goa, K. L., and Benfield P., (1989) S-Adenosyl-1-methionine: a review of its pharmacological properties and therapeutic potential in liver dysfunction and affective disorders in relation to its physiological role in cell metabolism. Drugs. 38, 389-416), arthritis (Di Padova C, (1987) S-adenosyl-1-methionine in the treatment of osteoarthritis: review of the clinical studies. Am J. Med. 83, (Suppl. 5), 6-65), and depression (Kagan, B, Sultzer D. L., Rosenlicht N and Gerner R. (1990) Oral S-adenosylmethionine in depression: a randomized, double-blind, placebo-controlled trial. Am. J. Psychiatry 147, 591-595.) Alzheimer""s patients have reduced cerebral spinal fluid levels of S-adenosyl-1-methionine (Bottiglieri et al, (1990) Cerebrospinal fluid S-adenosyl-1-methionine in depression and dementia: effects of treatment with parenteral and oral S-adenosyl-1-methionine. J. Neurol. Neurosurg. Psychiatry 53, 1096-1098.) In a preliminary study, SAM was able to produce cognitive improvement in patients with Alzheimer""s disease. (Bottiglieri et al (1994) The clinical potential of admetionine (S-adenosyl-1-methionine) in neurological disorders. Drugs 48, 137-152.) SAM-e brain levels in patients with Alzheimer""s disease are also severely decreased. (Morrison et al, (1996) Brain S-adenosylnethionine levels are severely decreased in Alzheimer""s disease, Journal of Neurochemistry, 67, 1328-1331. Patients with Parkinson""s disease have also been shown to have significantly decreased blood levels of SAM. (Cheng et al, (1997) Levels of L-methionine S-adenosyltransferase activity in erythrocytes and concentrations of S-adenosylmethionine and S-adenosylhomocysteine in whole blood of patients with Parkinson""s disease. Experimental Neurology 145, 580-585.) Oral SAM-e administration to patients with and without liver disease has resulted in increases in liver glutathione levels. (Vendemiale G et al, Effect of oral S-adenosyl-1-methionine on hepatic glutathione in patients with liver disease. Scand J Gastroenterol 1989;24:407-15. Oral administration of SAM-e to patients with suffering from intaahepatic cholestasis had improvements in both the pruritus as well as the biochemical markers of cholestasis. (Giudici et al, The use of admetionine (SAM-e) in the treatment of cholestatic liver disorders. Meta-analysis of clinical trials. In: Mato et al editors. Methionine Metabolism: Molecular Mechanism and Clinical Implications. Madrid: CSIC Press; 1992 pp 67-79.) Oral SAM-e administration to patients suffering from primary fibromyalgia resulted in significant improvement after a short term trial. (Tavoni et al, Evaluation of S-adenosylmethionine in Primary Fibromyalgia. The American Journal of Medicine, Vol 83 (suppl 5A), pp 107-110, 1987.)
SAM-e is clinically useful in many apparently unrelated areas because of its important function in basic metabolic processes. One of its most string clinical uses is in the treatment of alcoholic liver cirrhosis that, until now, remained medically untreatable. Mato et al, in 1999, demonstrated the ability of oral SAM in alcoholic liver cirrhosis to decrease the overall mortality and/or progression to liver transplant by 29% vs 12% as compared with a placebo treated group. (Mato et al, (1999) S-adenosylmethionine in alcohol liver cirrhosis: a randomized, placebo-controlled, double blind, multi-center clinical trial, Journal of Hepatology, 30, 1081-1089.) The extensive clinical use of SAM-e has proven its efficacy as well as its absence of toxicity in a number of different clinical conditions. Indeed, further basic science as well as clinical studies on this very important molecule may elucidate new uses for SAM-e in medicine.
SAM-e, however, presents certain difficult problems in terms of its stability at ambient temperature that result in degradation of the molecule to undesirable degradation products. SAM-e has therefore been the subject of numerous patents directed both towards the obtaining of new stable salts, and towards the provision of preparation processes which can be implemented on an industrial scale. There exist numerous patents disclosing many new salts of SAM-e but none discloses polycation salts such as chitosan salts of SAM-e. The following are representative patents of SAM-e salts currently on the pharmaceutical marketplace: Gennari, U.S. Pat. No. 5,102,791 Apr. 7, 1992, discloses, among others, a 1,4 butanedisulfonate salt of SAM-e but not polycation salts such as chitosan salts of SAM-e or of other SAM-e salts. Fiecchi, U.S. Pat. No. 4,028,183, Jun. 7, 1977, discloses, among others, p-toluene sulfonate as a means to stabilize the SAM-e molecule but does not disclose polycation salts such as chitosan salts of SAM-e or a salt of SAM-e. Kozaki et al, U.S. Pat. No. 4369177, Jan. 18, 1983, discloses stable compositions of SAM-e and SAM-e salts using a salt of a bivalent or trivalent metal but does not disclose the use of polycation salts such as chitosan salts of SAM-e or a salt of SAM-e. Zappia, U.S. Pat. No. 4764603, Aug. 16, 1988, discloses the use of polyanions such as polyphosphates, polyvinylsulfonates-sulfates or phosphates, polyacrylates, and polystyrene sulfonates. However, this patent does not disclose the use of a polycation salts such as chitosan salts of SAM-e or of SAM-e salts.
Administration of new SAM-e salts of the present invention would have significant utility over a wide range of disorders or conditions associated with low levels of SAM-e. These new salts would not cause gastrointestinal upset often associated with the current SAM-e salts. In this regard, and in view of the molecular instability of SAM-e at room temperature over time, it has been suggested that a more ideal salt of SAM-e would be able to withstand the conditions of room temperature over long periods of time which would duplicate the shelf life conditions under which these new SAM-e salts would be stored.
Accordingly, there is need in the art for new, stable salts of SAM-e as well as methods related to the use of such salts to increase blood and other tissue and fluid levels of SAM-e and to treat conditions which result from low blood and tissue levels of SAM-e. There is also a need in the art for synthetic routes to make such new salts. The author of this present invention fulfills these needs and provides further related advantages.
Briefly stated, the present invention discloses new, stable salts of SAM-e, methods for the use thereof and synthetic methods for their preparation. These new salts of SAM-e of this present invention have utility in increasing blood and other tissue or fluid levels of SAM-e, as well as treating or preventing a wide variety of conditions associated with low blood or other tissue or fluid levels of SAM-e. Thus in one embodiment, a new SAM-e salt is administered to a warm-blooded animal in need thereof to increase SAM-e levels. In another embodiment, a new SAM-e salt is administered to a warm blooded animal in need thereof to prevent or treat a condition associated with low levels of SAM-e. In yet a further embodiment, a new SAM-e salt is administered to a warm blooded animal in need thereof to prevent and or treat the following conditions: aging, aging of the skin, Alzheimer""s disease, arthritis, both as an anti-inflamrnatory as well as to promote new cartilage formation, nerve damage associated with HIV/AIDS, anxiety, obsessive compulsive disorder, attention deficit disorder and ADHD, sleep regulation, organ preservation for transplant industry, treatment of dyslipidemias, excess sebum production, migraines, prevention and treatment of bile dysfunction caused by pregnancy and use of contraceptive medications, cancer, depression, acute and chronic liver disease, cirrhosis of the liver, ischemic reperfusion injury of stroke as well as organ ischemic reperfusion in transplant technology, Parkinson""s disease, memory disturbances, intrahepatic cholestasis, inflammation, pain and to counteract the decrease in SAM-e caused by various cancer drugs.
As mentioned above, this invention is generally directed to new salts of SAM-e. Such new SAM-e salts when administered to a warm blooded animal in need thereof have utility in the prevention or treatment of conditions associated with low levels of SAM-e in warm blooded animals, including humans.
As used herein, the term xe2x80x9cconditionsxe2x80x9d includes diseases, injuries, disorders, indications and/or afflictions that are associated with decreased levels of SAM-e. The term xe2x80x9ctreatxe2x80x9d or xe2x80x9ctreatmentxe2x80x9d means that the symptoms associated with one or more conditions associated with low levels of SAM-e are alleviated or reduced in severity or frequency and the term xe2x80x9cpreventxe2x80x9d means that subsequent occurrences of such symptoms are avoided or that the frequency between such occurrences is prolonged.